EP3167873B1 - Aqueous solution of condensation products of taurinamide and methylene glycol for use as anti-infective agent in the implantation of devices in cardiac surgery - Google Patents

Description

The present invention relates to the enhancement of the therapeutic success of cardiac surgery implants, particularly implants of medical devices, which are grouped under the term "implantable electronic devices for the treatment of cardiovascular diseases". In the relevant medical literature, which is predominantly English-language, the generic terms "cardiac-implantable electrophysiological devices" or "cardiovascular implantable electronic devices", abbreviated CIEDs, are used for these devices as a rule. The term "cardiac rhythm management device", abbreviated CRMD, is also used.

Devices that are grouped under any of these terms include, without the following list exhaustive, various types of pacemakers, implantable cardioverter defibrillators (abbreviated ICDs), cardiac resynchronization therapy defibrillators (cardiac resynchronization therapy -defibrillator, abbreviated CRT-D), subcutaneous implantable cardioverter-defibrillators (subcutaneous implantable cardioverter-defibrillator, abbreviated S-ICD) and implanted monitoring devices for diagnostic purposes.

Since the advantageous clinical results achieved by the application of the invention of the present application have hitherto mainly been demonstrated in the field of surgical implantation of cardiac pacemakers, the successes and the practice of the invention will be described in the following description with reference to FIGS Implantation of pacemakers explained.

Cardiac pacemakers serve to arrhythmia, e.g. a slowing of heart activity (bradycardia), to remedy by electrical stimulation of the heart. Depending on the manufacturer and the particular application, pacemakers are available in various designs (for example with one or more electrodes or probes, where unipolar or bipolar electrodes, so-called anchor electrodes, screw electrodes, straight or pre-bent electrode and VDD electrodes are known).

The basic elements of a cardiac pacemaker include a housing (or aggregate), which is typically made of stainless steel or titanium today, containing the batteries and electronics needed to generate the electrical impulses and having terminals for one or more electrodes or probes. The housing is hermetically sealed, e.g. by laser welding, and has very smooth, polished surfaces. The electrodes or probes connect to the heart, deliver pacing pulses and monitor ECG signals.

To connect the inserted into the heart chamber and / or the atrium inert electrodes with the housing of the pacemaker electrode cables serve with a metallic conductor, which is surrounded by a plastic insulation, usually a polyurethane.

The pacemaker cases are about the size of a large coin or a matchbox.

Pacemakers are used as part of a minor surgical procedure. The electrodes or probes are advanced without general anesthesia with dissociative anesthesia through a skin incision via a vein into the heart (to the right heart, atrium and possibly also the chamber). Thereafter, when properly positioned, the pacemaker housing (aggregate) is connected to the probes and implanted in a pocket, usually in the chest wall below the collarbone.

Through the development and use of CIEDs, e.g. Cardiac pacemakers, it has been achieved that the morbidity and mortality characteristics have improved significantly due to heart disease in the population. The number of implantations of CIEDs, e.g. Cardiac pacemakers have therefore increased significantly in recent decades or years.

However, it has been found that at the same time certain problems attributable to infections in the area of the implanted devices have exacerbated, compared with the increase in the number of implanted CIEDs disproportionately. The problems are referred to as device-related infections or devicerelated infections, DRIs for short.

In a number of recent publications, several authors are concerned with DRIs and their prevention and therapy. By way of example, the publications of Dong Heun Lee et al., "Differences in Mortality Council between Pocket and Nonpocket Cardiovascular Implantable Electronic Device Infection ", in: PACE 2015; 00: 1-8 ; Gareth J. Padfield et al., "Cardiac implantable electronic device infections", Heart Rhythm 2015; 0: -2-13 ; Martin Rohacek et al., "Cardiovascular implantable electronic device infections: associated risk factors and prevention", Swiss Med Wkly. 2015; 145: w15157 ; Avirup Guha et al., Cardiac implantable device infection in patients with end-stage renal disease, Heart Rhythm 2015; 0: 0-7 ; Achana Kodali et al., "A Case of Late Implantable Cardiac Device Infection with Aspergillus in an Immunocompetent Host," AJ Case Rep, 2015; 16: 520-523 ; Jonathan AT Sandoe et al., "Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection." Report of a joint working party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE) ", J. Antimicrob. Chemother 2015; 70: 325-359 ,

In the publication J. Alberto Lopez, "Conservative management of infected pacemakers and implantable defibrillator sites with a closed antimicrobial irrigation system", Europace (2013), 15, 541-545 , the overall problem is explained and a procedure for the case of an infection has been described, namely a flush (infusion, irrigation) of the infected pacemaker bag and the removed pacemaker housing with an antibiotic solution (vancomycin / gentamicin solution).

Considerations are being considered in the cited publications as to what the increased DRI numbers are and what options could be offered for reducing the number of infections, eg by changing the surgical technique and / or by using suitable medicines. For details, see the content said writings, and the older publications mentioned therein, referenced.

Measures that have been investigated for possible reduction in the number of infections include perioperative antibiotic prophylaxis in the form of an intravenous injection of an antibiotic, e.g. of Cefazolin, just prior to surgery in the patient and, if necessary, again afterwards. In an attempt to improve the infection rate by irrigation (wound irrigation) with the antiseptic povidone-iodine (Braunol) no significant improvement was observed. In order to reduce the infection, an antibacterial infiltrated tissue envelope has also already been tested for the device to be implanted, although improvements indicated that the results still require further verification. The use of hydrogen peroxide as an antibacterial (bactericidal) agent, e.g. in the form of a soaked gauze is also tested.

In a publication of Georg Marsch et al., "Prevention of pacemaker infections with perioperative antimicrobial treatment: an in vitro study", in Europace (2014), 16, 604-611 , the authors investigated whether antibacterial pretreatment of pacemaker housings with antibiotics (vancomycin, daptomycin, cefuroxime, tazobac or nebacetin) or antiseptics (povidone-iodine or octenidine dihydrochloride) could be a measure to reduce the number of device-related infections (DRIs). To this end, they tested in vitro the effect of solutions of antibiotics and antiseptics on titanium platelets (0.4 cm ² ) that they produced by cutting titanium pacemaker housings. In particular, the antibiotic nebacetin gave promising results, while other antibiotics or the two antiseptics tested were either not convincing showed antibacterial effects or proved to be cell-damaging, which represents a serious disadvantage in terms of wound healing after surgery.

Thus, there continues to be a need for means to improve the therapeutic success of implantation of CIEDs by reducing or avoiding the occurrence of device-related infections (DRIs).

The invention will be further described by the appended claims in conjunction with the following more detailed explanation of various aspects thereof.

The object is achieved by an aqueous solution for use according to claim 1. Advantageous developments of the invention can be found in the subclaims 2 to 5.

The invention relates to the use of an aqueous solution of condensation products of taurinamide and methylene glycol and their salts, in particular taurolidine, taurultam or cyclotaurolidine, as an antiinfective agent in the implantation of implantable devices in cardiac surgery, in particular in the implantation of an implantable electronic device selected is comprised of cardiac pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy defibrillators, subcutaneously implantable cardioverter defibrillators, and implantable electronic monitoring devices for diagnostic purposes.

The aqueous solution used contains as antimicrobial active substance taurolidine and / or its hydrolysis products in a concentration of 0.5 to 3 wt .-% or dissolved taurultam in a concentration of 1 to 7.5 wt .-%, as well as a solubilizer for the antimicrobial active substance and / or as the wetting of metal and plastic surfaces promoting agent, a water-miscible, physiologically acceptable polymer. The water-miscible polymer is preferably polyvinyl pyrrolidone (PVP, povidone) having an average molecular weight of less than 30,000, preferably less than 10,000, for example between 7,000 and 9,000, and is preferably present in the solution in amounts of from 3 to 7% by weight, for example 5 wt .-%, present.

In use, the usual procedure is to place the implantable device into the solution prior to implantation for the time required to achieve the desired optimal antimicrobial effect and completely wet all surfaces of the device, according to a preferred practice for about 20 minutes, and thereafter the implantable device, eg the case of a cardiac pacemaker is implanted with a film of the aqueous solution on its surface in the bag prepared by the operating surgeon.

The bag is then rinsed with the remaining solution (about 100 ml).

The application of the invention, as demonstrated below with reference to clinical trial results, results in the improvement of therapeutic success and reduction of infections in the implantation of implantable electronic devices in cardiac surgery.

The term "condensation products of taurinamide and methylene glycol and salts thereof" refers to compounds which comprise the most prominent representatives of the compound taurolidine, for which a particularly advantageous preparation in a highly pure form without undesired By-products is described in the European patent EP 0 863 133 B1 or the corresponding U.S. Patent US 5,889,189 ,

In the case of the compound taurolidine, the molecular ratio of taurinamide to methylene glycol (methanediol, formaldehyde hydrate) is 2: 3 or 1: 1.5. It is known that taurolidine hydrolyzes upon dissolution in an aqueous medium, so that it is difficult to detect taurolidine in the aqueous solution per se. It is assumed that the aqueous solution mainly contains the compounds taurultam and methylol taurultam, in which the ratio of taurine amide to methylene glycol is 1: 1 or 1: 2.

Instead of taurolidine, it is also possible to assume a compound designated as cyclotaurolidine, its preparation and properties in the European patent EP 1 882 476 or the corresponding U.S. Patent US 7,820,651 are described. The full content of said patents, in which the condensation of taurine amide and methylene glycol at different molar ratios of the partners of the condensation reaction is described in more detail, is expressly referred to supplement the present description.

Since taurolidine is the best known and in practice most important condensation product of taurinamide and methylene glycol and its designation is sometimes even equated with the whole group of condensation products, the invention will be described below using the term "taurolidine" for the antibacterial active substance. A limitation of the teaching of the invention by a description with reference to "taurolidine" is not intended.

Taurolidine is known to have its antimicrobial effect on a transfer of methylol groups to Cell wall components of bacteria is based. It is also known that taurolidine develops its full antibacterial effect only at a contact time of its solution with the microorganisms, eg bacteria-contaminated surfaces, of a few minutes, typically within about 10 minutes or more. It has also been found to be effective against biofilms against which other antiseptics or antibiotics show no or only poor efficacy.

There has been no report of any development of resistance to taurolidine, which is a major advantage over the use of antibiotics, which usually have resistance problems after a period of use. It has also been found that taurolidine can also be used against the problematic (multi) resistant nosocomial pathogens, e.g. MRSA (Methicillin-Resistant Staphylococcus aureus) and VRE (Vancomycin-resistant Enterococci) and others, under the umbrella term ESKAPE pathogens, are fully effective.

Aqueous solutions of taurolidine are known and are already being used successfully in the healthcare sector. A particularly important use of such solutions is as medical devices in the form of so-called "lock solutions" with which catheters are filled for the duration of use breaks, for example between hemodialysis treatments or during pauses in the supply of medicaments or nutrient solutions. Further details of this type of use can be found in the patents already mentioned above EP 0 863 133 and EP 1 882 476 as well as in the patents EP 1 089 738 such as EP 1 814 562 whose contents are referred to in greater detail. A product range for use as a lock solution are, for example, the TauroPharm GmbH products which are commercially available under the TauroLock® brand.

In addition, aqueous solutions of taurolidine are also used as medicaments, as instillations and surgical rinsing solutions with Taurolidingehalten of 0.5 and 2.0 wt .-%, which also contain as a solubilizer polyvinylpyrrolidone. Such products are the Taurolin® branded products (Taurolin® (Taurolidine "Geistlich") 2% instillation solution, Taurolin® (Taurolidine "Geistlich") 0.5% Surgical Rinse Solution, Taurolin® Ringer 0.5%) and the product Taurolidine Nova 2.0% of TauroPharm GmbH.

Taurolidine Nova 2.0% is declared as a broad-spectrum chemotherapeutic agent for use in prolonged purulent inflammation of the peritoneum, most of which are caused by microorganisms such as bacteria from the gastrointestinal tract, the stool and the urinary tract (local or diffuse Peritonitis of purulent or stercoral origin). The product contains in 1 ml of solution 20 mg taurolidine in water for injections, and as other ingredients sodium hydroxide solution for pH adjustment and povidone.

The results of the new clinical use for the purposes of the present invention described below were obtained using a solution containing 2% by weight of taurolidine.

Clinical results:

In a cardiological ward of an academic teaching hospital, where pacemakers are implanted routinely and in large numbers of patients, it has been the practice to treat the pacemaker housings to be implanted with a solution of hydrogen peroxide during implantation while simultaneously permitting wound irrigation with hydrogen peroxide. It comes to the release of oxygen and strong foaming. Despite the bactericidal properties of dilute hydrogen peroxide, the effect of the treatment as infection prophylaxis in the implantation of devices is not verified.

Cardiac pacemaker implantation has been reported to be infected despite hydrogen peroxide treatment after implantation, after a shorter or longer time within the 2 month revision period. An infection rate of about 9 infections per 60 implantations or 10 infections per 70 implantations was observed.

On the other hand, according to the procedure of the invention, in which the pacemaker to be implanted was placed in a solution of 2.0% by weight of taurolidine in water for injection for about 20 minutes prior to implantation, then the implantable device, e.g. the case of a cardiac pacemaker implanted with a film of the aqueous solution on its surface in the bag prepared by the surgeon and then rinsing the bag with the remaining solution (about 100 ml), no infections were observed in a comparable number of implants ,

Pacemaker implantations using a 2.0% strength by weight aqueous taurolidine solution according to the invention are tabulated in Table 1 below. The table shows the findings for 45 implantations, including 9 cases of replacement of one aggregate with a new one, occurring between February and September 2015, in all cases the stated 2.0% by weight aqueous taurolidine solution as described was used.

In the table are the patients with initials derived from their first names and their year of birth individualized. In addition, the duration of surgery and the implanted pacemaker / ICD system are indicated. Since the individual implantations took place over a relatively long period of time, they are of different lengths at the time of filing the present application, ie the monitoring period is somewhat different for the different implantations.

Of the patients in Table 1, 12 were female and 33 were male. The age of the patients was between 94 years and 47 years.

Until the filing date of the present application, unlike the cases of hydrogen peroxide treatment, no infection was observed in any of the patients. Due to the apparent superiority of a procedure according to the invention, the practice has been completely changed to its application and, for ethical reasons, no further figures are to be expected for treatments with hydrogen peroxide.

In the application of the invention, confidentiality has been agreed and maintained between all persons involved until today.

In addition to the fact that the procedure according to the invention, according to all available findings, offers superior protection against infections (DRIs), good, undisturbed wound healing is also observed.

It is also within the scope of the present invention to use the aqueous taurolidine solutions which can be used according to the invention within the context of a technique in which - as in the publication by J. Alberto Lopez mentioned at the beginning - rinsing of infected pacemaker pouches takes place. Although the invention is described in terms of CIEs in the present application, ie, an area in which beneficial clinical results have already been demonstrated, the inventors believe that similar benefits in terms of infection prevention are also implanted in other cardiac surgery Detect devices without electronic or electrophysiological components, especially in artificial heart valves. <u> Table 1 </ u> patient Year of birth operation time Implanted System * FR 1937 1 h 42 min CRT-D DDD MO 1958 1 h 17 min DDD II-SM BA 1945 33 min DDD-SM ON 1957 36 min VVI_ICD KA 1933 15 minutes VVI_ICD FR2 1960 19 min VVI_ICD BE 1936 12 min CRT-D DDD JO 1952 15 minutes DDD-SM MX 1937 32 min VVI ICD TH 1927 8 min DDD-SM JO2 1928 15 minutes DDD-SM KL 1937 31 min DDD-SM MA 1953 20 min VVI ICD MT 1956 115 min VVI ICD LU 1945 20 min VVI ICD WE 1943 82 min CRT-D DDD RO 1968 45 min DDD-SM IO3 1937 41 min DDD-SM PE 1961 28 min VVI ICD HE 1947 48 min DDD-ICD BR 1939 84 min DDD-ICD JH 1934 25 min VVI SM HI 1923 28 min VVI SM JH2 1938 24 min VVI SM HN 1940 33 min DDD + RV probe WE2 1931 17 min VVI SM JO4 1941 85 min CRT-D VVI KA2 1932 60 min DDD-SM RE 1948 55 min DDD-SM AD 1937 31 min VVI ICD For example, 1953 13 min VVI ICD SI 1962 32 min VVI ICD FR3 1942 53 min VVI ICD FI 1937 179 min CRT-D HA 1938 185 min CRT-D JP 1966 70 min VVI ICD KT 1921 22 min VVI ICD AL 1938 87 min VVI ICD IR 1944 64 min CRT-P TH2 1934 110 min DDD-SM FR4 1934 76 min CRT-D MA2 1931 91 min DDD-SM SF 1952 92 min CRT-D FR5 1942 40 min DDD-SM MR 1960 29 min VVI ICD

Explanatory notes to Table 1: Abbreviations:

SM

Pacemaker

ICD

Implantable Cardiac Device

CRT-D

Cardiac Resynchronization Therapy - Defibrillator

• Die erste Stelle gibt den Stimulationsort an. Hierbei steht V für Ventrikel (Kammer), A für Atrium (Vorhof) und D für beide.
• Die zweite gibt den Ort der Signalaufnahme an. Die Abkürzungen entsprechen denen für die erste Stelle.
• Die dritte Stelle gibt den Modus an. Hierbei steht I für inhibiert, T für getriggert (auslösend), und D für durch den Vorhof getriggert und die Kammer inhibiert.
• Die vierte Stelle liefert Informationen über die Art der Programmierung, z.B. R für frequenzmoduliert (durch die Vorhoffrequenz variiert).
• Die fünfte Stelle gibt Auskunft über einen möglichen implantierten (enthaltenen) AICD (automatic implantable cardioverter defibrilator.

To further identify and distinguish between different types of devices, a single nomenclature is used, in which pacemakers are identified by a three to five-letter abbreviation:

• The first digit indicates the stimulation site. Where V is the ventricle (chamber), A is the atrium (atrium), and D is both.
• The second indicates the location of the signal recording. The abbreviations correspond to those for the first digit.
• The third digit indicates the mode. Here, I is inhibited, T is triggered (triggering), and D is triggered by the atria and inhibits the chamber.
• The fourth digit provides information about the type of programming, eg R for frequency modulated (varies by the atrial rate).
• The fifth digit provides information about a possible implanted (included) AICD (automatic implantable cardioverter defibrillator.

Typical, commonly used abbreviations are DDD and VVI.

Claims (5)

1. Aqueous solution of condensation products of taurinamide and methylene glycol and the salts thereof, which substantially contains only taurolidine and/or the hydrolysis products thereof in a concentration of 0.5 to 3 wt% or dissolved taurultam in a concentration of 1 to 7,5 wt% and, in addition, a water-miscible, physiologically tolerated polymer in the form of polyvinyl pyrrolidone (PVP, povidone) having an average molecular weight of less than 30,000 as a solubilizing agent and/or an agent promoting the wetting of metal and plastic surfaces, which is present in the solution in amounts of 3 to 7 wt%,
   for use as an anti-infective agent in the implantation of an implantable electronic device in cardiac surgery according to a method in which the aqueous solution is used for the surface treatment of the implantable electronic device prior to implantation and the implantable electronic device is implanted with a film of an aqueous solution on the surface thereof.
2. Aqueous solution according to claim 1 for use according to claim 1, characterized in that it has been prepared by dissolving taurolidine, taurultam or cyclotaurolidine.
3. Aqueous solution according to claim 1 for use according to claim 1, characterized in that the water-miscible polymer is polyvinyl pyrrolidone (PVP, povidone) having an average molecular weight of less than 10,000, for example between 7,000 and 9,000, and is present in the solution in amounts of 3 to 7 wt%, for example 5 wt%.
4. Aqueous solution according to any one of claims 1 to 3 for use according to claim 1, characterized in that the implantable electronic device is selected from pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy defibrillators, subcutaneously implantable cardioverter defibrillators and implantable electronic monitoring devices for diagnostic purposes.
5. Aqueous solution according to any of claims 1 to 4 for use according to claim 1, wherein the implantable electronic device is placed in the solution prior to implantation for the time required to achieve the desired antimicrobial effect and complete wetting of all surfaces of the device, and the implantable device is implanted with a film of the aqueous solution on the surface thereof.